Medical Journal of Zambia, Vol. 47 (1): 63 - 69 (2020)

CASE REPORT Issues of diagnosing ROHHAD Syndrome in a 2-year-old girl : A Case Report and Review of Literature

L.V. Pushko1, T.A. Gutyrchik2, D.Yu. Ovsyannikov1, 2 N.A. Gutyrchik1, N.I. Petruk1, N.A.Petrova2, Mwela Bupe Mumba1

1Department of Paediatrics and Child Health, Peoples' Friendship University of Russia; 2Morozovskaya Children's Hospital, Moscow, Russia.

ABSTRACT disease is respiratory disorders in the form of sleep apnea, alveolar hypoventilation [3-4]. In contrast to We present a clinical case of ROHHAD syndrome. the syndrome of congenital Central alveolar In this article we discuss the rare occurrence of this hypoventilation (Ondine's curse), ROHHAD- pathology and, as a result, the issues encountered in syndrome is characterized by late-onset, severe the diagnosis and treatment of such children. Thus, hypothalamic and autonomic disorders, the absence in highlighting the problem, the team of Authors set of mutations in PHOX2B gene, leading to a the goal of emphasizing the importance of timely congenital syndrome [5-7]. diagnosis, as well as correctly selecting From birth, children with ROHHAD-syndrome comprehensive treatment for children with grow and develop physiologically, but at the age of ROHHAD syndrome. 1.5–7 years, a sharp increase in body weight begins – INTRODUCTION AND LITERATURE rapidly progressing obesity, weight gain for 6-12 REVIEW months, it can be from 10 to 20 kg- as a result of hypothalamic dysfunction and polyphagia [3, 8, 9]. ROHHAD is an acronym for rapid-onset obesity After rapid weight gain, children develop respiratory (RO) with hypothalamic dysregulation (H), disorders in the form of obstructive apnea and hypoventilation (H) and autonomic dysregulation hypoventilation due to loss of vegetative control (AD). According to the international classification over the breathing process. Children with this of sleep disorders ICSD-3 2014, it is a type of syndrome develop alveolar hypoventilation with sleeping- dependent hypoventilation and is a rare hypercapnia and hypoxemia (hypoxemia has an genetic disease that manifests after 2 years of life in auxiliary diagnostic value) during sleep. However, previously healthy children [1-2]. There are about the development of hypoventilation is not always 100 clinical cases with this syndrome in the world obvious, since the child does not feel it, as in the [3]. The abbreviation ROHHAD describes a typical syndrome of congenital Central alveolar sequence of symptoms and stands for rapidly hypoventilation. In more severe patients, progressive Rapid-onset Obesity with hypothalamic hypoventilation may also occur while awake, which dysregulation, Hypoventilation and autonomic can lead to respiratory and [4]. dysfunction [1-3]. A dangerous manifestation of the Hypothalamic dysfunction is manifested by fluid- Corresponding author: electrolyte imbalances in form of Hypo - or Mwela Bupe Mumba Department of Paediatrics and Child Health, Peoples' Keywords: ROHHAD syndrome, rapid-onset obesity, Friendship University of Russia hypothalamic dysregulation, hypoventilation, Autonomic E-mail: [email protected] dysregulation, the acid-base balance of the blood

63 Medical Journal of Zambia, Vol. 47 (1): 63 - 69 (2020) as a result of vasopressin deficiency day. Detection of the level of PaCO2>50 mm Hg and or reduced secretion of antidiuretic hormone; high SpO2<95% and allows to establish the diagnosis of levels of prolactin; low levels of thyroid hormones, "awake" hypoventilation [4]. In the development of cortisol, and somatotropic hormone; delay or early sudden obesity, a targeted assessment of ventilation puberty; impaired glucose tolerance. Vegetative by pulse oximetry and capnography is necessary dysfunction manifests itself as eye changes (lack of during sleep and when awake. It is recommended to response of the pupils to light, strabismus); conduct a comprehensive examination: a detailed violations of intestinal motility, which leads to physiological assessment of breathing when awake constipation or diarrhea; episodes of increased body as well as during sleep, a comprehensive temperature, sweating; decreased pain sensitivity; cardiological assessment, including 72-hour Holter bradycardia. Patients with ROHHAD-syndrome are monitoring of electrocardiography, veloergometry also characterized by behavioral disorders, mood (physical tolerance or exercise test) and and mental retardation, obsessive disorders with echocardiography (with the determination of episodes of psychosis, and autistic disorders. pressure in the pulmonary artery due to the However, a surprisingly high percentage of children with ROHHAD syndrome have a normal or high possibility of developing pulmonary hypertension level of intelligence. Some of them develop due to hypoxemia), neurocognitive testing to assess seizures, which may be caused by hypoxemia due to intellectual development as a marker of neurological insufficient respiratory protection supports. status. It is also necessary to examine the endocrine system to determine the symptoms of hypothalamic Approximately 40% of ROHHAD - syndrome dysfunction and/or pituitary pathologies. It is also Patients develop tumors that occur in the neural important that if hypercalcemic dehydration is crest, such as ganglioneuroblastomas. In this regard, noted, one should determine the secretion of the it was proposed to rename ROHHAD-syndrome to antidiuretic hormone before assuming the diagnosis ROHHADNET-syndrome (Rapid-onset Obesity of " ". Obesity can alter the Hypoventilation Hypothalamic Autonomous secretion of growth hormone and the level of insulin- Dysregulation Neural Endocrinological Tumor) to like growth factor-1 (IGF-1), which should be taken include these tumors in the diagnostic criteria, but into account when evaluating the function of growth this was accepted only for patients who develop hormone. It is necessary to take into account such these tumors. The development of tumors is complications of obesity as fatty liver dystrophy, associated with mutations in the PHOX2B gene. impaired lipid metabolism or diabetes mellitus. It is important to conduct computer tomography of the To confirm ROHHAD-syndrome, the following chest and abdominal organs to detect tumors of the criteria must be present: 1) the onset of rapid and neural crest [10]. extreme weight gain after 1.5 years (usually after 2- 7 years) in a previously healthy child; 2) evidence of Treatment of ROHHAD-syndrome is currently dysfunction; 3) alveolar symptomatic. Obesity is extremely difficult to hypoventilation; 4) features of vegetative control through diet and exercise, and measures are dysregulation. needed to prevent further weight gain. Since patients with ROHHAD-syndrome do not improve their Additional screening for ROHHAD syndrome breathing adequately during exercise, it is important includes nighttime polysomnography to determine to recommend moderate loads whose safe any signs of obstructive sleep apnea. Daytime parameters are based on monitoring the PaCO2 level hypoventilation can be diagnosed by monitoring and pulse oximetry during training. levels of carbon dioxide (PaCO2) and blood oxygen saturation (peripheral saturation, SpO2) during the

64 Medical Journal of Zambia, Vol. 47 (1): 63 - 69 (2020)

Hypothalamus dysfunction observed in these Other assisted breathing techniques, such as patients should be evaluated and treated by a diaphragm stimulation, may have limited success pediatric endocrinologist. Treatment methods may due to obesity-associated with ROHHAD- include hormone replacement therapy, a strict fluid syndrome, but they should be considered in some intake regime, and other measures. It is shown that patients. the introduction of growth hormone improves body Patients with ROHHAD syndrome are at risk of composition, and the use of dopamine agonists to bradycardia, which can be eliminated only after the normalize prolactin levels does not change the installation of a pacemaker. The lack of temperature clinical course of the disease [11]. control requires careful regulation of the ambient One of the main problems in patients with temperature and attention to low body temperatures. ROHHAD syndrome is a violation of respiratory For chronic constipation due to impaired motility of control. It is important to remember that the isolated the gastrointestinal tract, laxatives are prescribed. supply of oxygen does not eliminate Tumors from the neural crest require surgical hypoventilation. Alveolar hypoventilation requires removal, however, to date, surgical removal of invasive or non-invasive ventilation to ensure neural crest tumors has not reduced the deployment adequate ventilation, prevent atelectasis and of the ROHHAD syndrome phenotype and has not attachment of lower respiratory tract infection, as caused recovery from the disease. An well as due to the risk of apnea and acute interdisciplinary team of specialists, including an cardiorespiratory insufficiency, while CPAP therapy endocrinologist, pulmonologist, cardiologist, (Constant Positive Airway Pressure, continuous intensive care doctor, respiratory specialist, positive airway pressure) is effective for obstructive otorhinolaryngologist, surgeon, oncologist, sleep apnea syndrome, respiratory disorders due to gastroenterologist, neurologist, ophthalmologist, upper respiratory tract obstruction [13]. psychologist, psychiatrist, speech therapist, and Some children with ROHHAD syndrome may special education specialist, working together with initially need invasive ventilation only during sleep, the child and family to optimize care and quality of and then there is a need for constant support both life, is crucial for the successful management of during sleep and when awake. In children who need patients with ROHHAD-syndrome [12]. ventilation only at night, mask ventilation with two- CLINICAL CASE levels (bi-level) positive pressure can be performed. Those children who require a ventilator for 2 hours a Anamnesis vitae: a female child from II pregnancy, day are given ventilation through the tracheostomy II spontaneous vaginal delivery at 39 weeks [12]. gestation age. Bodyweight at birth 3560 g, length 53 cm. From the age of 2, the child began gaining For adequate development, children receiving weight significantly: (for 6 months, the increase in ventilation should be at home, but need to have a body weight was 5 kg). At the same time, there were ventilator at home, which has a provision for the complaints of dry cough, enuresis, and sweating. No availability of a backup ventilator, pulse oximeter, medical help was sought. In September 2018 (at 2 capnograph for transcutaneous PaCO2 monitoring years 7 months old), after contact with a patient with and an energy generator. Specialized service is an acute respiratory viral infection, the girl needed to control home ventilation, which is not yet developed a low-grade fever and a dry cough. After 4 developed in Russia. In recent years, it has become days, the body temperature increased to 38-41 0C, possible to patronize children by visiting hospice while the state of health decreased slightly. On an services. In many countries, such families are outpatient review, after two courses of antibacterial provided with night care staff [13].

65 Medical Journal of Zambia, Vol. 47 (1): 63 - 69 (2020) therapy (azithromycin, cefixime), there was no maximum of 32 ng/ml, the norm is 1.2–19.5 ng/ml) improvement, so she was admitted to the hospital was detected during repeated blood tests, while with the diagnosis: "Acute respiratory viral there were no clinical manifestations of infection. Community-acquired pneumonia?” hyperprolactinemia. Diabetes insipidus was excluded. In the analysis of urine according to Upon admission, the condition became severe due zimnitsky's test, the relative density of urine from to intoxication and fever. A subcutaneous fat layer 1005 to 1020, isosthenuria was absent. Indicators of developed excessively and was evenly distributed. the acid-base state of blood and blood gases were On auscultation of the lungs, wheezes and rhonchi monitored twice daily, PaCO2 increased to 88 mm were heard. Tachypnea up to 64 breaths per minute. Hg. PaO2 decreased to 25.2 mmHg. However, SpO2 was 86-88% in room air and 99-100% when hypernatremia remained up to 156.2 mmol /l. oxygen was provided through nasal cannulas. The Markers of bacterial infection were not increased. child's condition deteriorated: she developed MRI examination of the brain with intravenous lethargy, confusion, and shortness of breath. contrast showed no signs of structural pathology. Laboratory results of acid-base state and Based on the conducted examinations, volume biochemical analysis of blood were as follows: formations of the hypothalamic-pituitary region blood pH 7.23–7.27, BE-12.3-10.4 mmol/l, sodium (MRI of the brain with intravenous contrast), 144-159 mmol/ l, potassium 3.35–4.52 mmol/l, volume formations of the thoracic cavity, abdominal chlorine 135-130 mmol/ l, glucose 4.6–5.9 mmol/l, cavity and retroperitoneal space (CT with contrast) calcium 1,8-2,1 mmol / l. in the General analysis of were excluded. Echocardiography- showed no urine: specific gravity 1025-1030. According to a structural changes of the heart and hemodynamics chest X-ray done on admission, pneumonia was were normal, the pressure in the pulmonary artery excluded. The child was treated with oxygen was also normal. On daily Holter monitoring, ECG therapy, infusion, diuretics, and symptomatic and blood pressure (BP), the heart rate and blood therapy. With treatment, the indicators of the acid- pressure were within normal range. EEG-signs of base state of the blood, sodium, and chlorine epileptiform activity was not detected. Infectious normalized, but there was no significant causes of fever (toxoplasmosis, yersiniosis, improvement in the condition of the child. Fever salmonellosis, herpesvirus infections, HIV, syphilis, persisted, and episodes of O2 desaturation at night. hepatitis B and C) were excluded. Blood cultures for Due to a history of long-term continuous use of sterility, showed no growth. Tuberculosis was antipyretic drugs, fever, electrolyte disorders, excluded (based on the results of the Mantoux respiratory failure, and background of significant reaction, Diaskintest). Oncohematological diseases weight gain, a preliminary diagnosis was made: were also excluded ( based on the results of bone "systemic hypothalamic-pituitary Pathology? marrow puncture, alpha-fetoprotein – within the Hyperosmolar syndrome. Decompensated normal range). There were no neuro infections metabolic acidosis, hyperthermic syndrome, (cerebrospinal fluid was normal, PCR and seeding ROHHAD-syndrome?". for flora were negative. A genetic study was She underwent a comprehensive examination. conducted. There were no mutations in the According to the results of laboratory tests, PHOX2B gene, indicating the syndrome of adrenocorticosteroid hormone, cortisol, thyroid congenital Central alveolar hypoventilation. hormones, thyroid-stimulating hormone, insulin, C- ROHHAD-syndrome was diagnosed based on the peptide, human chorionic gonadotropin in the blood patient history, clinical picture and results of serum were all within the normal range. A laboratory and instrumental findings (significant significant increase in the level of prolactin (up to a weight gain over 6 months, persistent fever without

66 Medical Journal of Zambia, Vol. 47 (1): 63 - 69 (2020) clinical and laboratory signs of bacterial infection, sleep) and during the day (when awake) a study was water-electrolyte disorders, desaturation when the conducted on acid-base balance of the blood (see child was awake (up to 88%) and during sleep-up to table), which was evidence of hypoxemia and 78% without O2 (in room air), hypercapnia and hypercapnia. On chest x-ray, community-acquired absence of mutation in the PHOX2B gene). pneumonia was diagnosed. Although the background of treatment was Table; Studies of acid-base balance of the blood at complex, there were a few positive dynamics like night and in the morning according to our results. the normalization of body temperature, correction Indicators T ime Standards of the blood electrolyte imbalance, and an 00:33 01:58 08:24 improvement in the severity of respiratory failure. pH (acidity) 7,37 7,34 7,33 7,35-7,45 In December 2018, the child was discharged with pO2 (partial oxygen 45,9 4 9,9 133,5 83-108 mm Hg. st. recommendations of oxygen therapy at night due to pressure) PCO2 (partial 59,5 55,7 53,5 32-48 mm Hg . st. normal PaCO2 indicators at discharge and pressure of carbon compliance of a diet with limited volume and caloric dioxide) content of food taken. cO2 (CT) (the 11,3 10,9 13,7 37-42 mm Hg. st. concentration of oxygen) (venous) On review as an outpatient, the child's condition cBE (base excess) 7,9 3,9 1,6 -2,9-0 mmol/l remained stable for 3 months. The level of SpO2 HCO3-c 33,2 29,6 27,5 24-28 mmol/l during the day remained within the normal range ((concentration of bicarbonate ions) (95-99%), at night she was on oxygen support. With bicarbonate - vein parent's adherence to diet changes, the child's body On 17.04.2019 there was deterioration in the acid- weight was controlled. However, during this period, base balance of the blood (decreased pH, increased fevers up to 38.5 C were noted three times. They hypercapnia), increased respiratory failure, and were controlled at home. fever – Respiratory support and antibacterial therapy On March 12, 2019, the patient presented to our were started. The child's condition continued to hospital with a fever of up to 40,0*C. After 3 days, deteriorate. Medical sedation with (diazepam, respiratory failure increased (SpO2 reduced to rocuronium)was done. On inspection, tactile stimuli 50%), and she had noisy breathing. The child was were negative. Fever was up to 41.0*c. The child admitted to the intensive care unit. Although she had was on ventilation through a nasotracheal intubation a constant supply of O2, SpO2 was 78%. On tube in the form of synchronized intermittent examination, she was sluggish, in a state of stun and mandatory ventilation (SIMV) with FiO2 45%, not fully oriented. On auscultation of the lungs positive end- of-expiration pressure (PEEP) +6 cm generalized dry and moist rales were present. She of water. On tracheal sanitization, an abundant also had pronounced shortness of breath and amount of Muco-purulent sputum was noted. tachycardia. Due the weakening of the swallowing Hemodynamics were stable. Blood pressure was reflex a nasal gastric tube was inserted, and the 110/57 mm Hg. heart rate 162 per minute. Repeated patient received enteral nutrition. Taking into MRI examinations of the brain were performed in account the long-lasting fever up to 40.0 and to the hospital to exclude ROHHADNET syndrome. exclude sepsis blood tests were performed No pathologies were detected, and there were no (procalcitonin <0.5 ng / ml). According to an acid- volume lesions (see picture 1). In an extended base blood test - she had compensated metabolic genetic study, mutations in SWAG candidate genes - acidosis, 118 mmol/l, and RET, GDNF, EDN3, BDNF, ASCL, PHOX2A, hypokalemia up to 2.4 mmol/l. At night (during GFRA1, BMP 2, ECE1 – were not detected.

67 Medical Journal of Zambia, Vol. 47 (1): 63 - 69 (2020)

during sleep and to continue diet changes. At present, the child's condition is satisfactory. There have been no fevers or episodes of desaturation when awake. During sleep, the child is on a non- invasive ventilator through a nasal mask with the above parameters. In General, therapy was positive. There have been satisfactory dynamics in growth rates and a decrease in the rate of weight gain due to diet changes. CONCLUSION ROHHAD-syndrome is currently a rare but actively studied disease. Due to the versatility of clinical manifestations, which often do not allow doctors to identify the main clinical symptom of the disease. The lack of reliable genetic criteria for ROHHAD- Picture 1. MRI of the child's brain (description in syndrome is a serious diagnostic problem for the text). pediatricians, along with other sleep disorders. This clinical presentation demonstrates the need to take a During the treatment, multicomponent therapy of good history and a thorough and comprehensive respiratory failure was performed. Hypothalamic examination. Joint examination and management of syndrome with vegetative-vascular disorders and such patients by a team of specialists is vital. The thermoregulation disorders, psychasthenic diagnostic criteria must include the detection of syndrome, negativism, and emotional hyper- PaCO2 during daytime and at night (when child is reactivity persisted. Gradually with therapy, awake and when asleep) – a key marker is a neuropsychological symptoms regressed and clear hypoventilation. Dynamic monitoring and consciousness was restored, she had adequate management of patient data provide ventilation and independent breathing when awake and fever oxygenation using invasive or non- invasive subsided, speech functions were restored, was able ventilation with mandatory monitoring of relevant to swallow, small and large motor skills were indicators (PaO2, PaCO2); with exception of restored, she was able to walk independently, but ROHHADNET-syndrome and pulmonary had a wide gait and psychoneurological hypertension, which was carried out in this patient. development of large motor skills were partially delayed. Taking into account the nature and REFERENCES specifics of the underlying disease, the child 1. Pushko LV, Gutyrchik TA, Ovsyannikov DYu, continued on non-invasive respiratory support Petrova NA, Teterkina AO, Gutyrchik NA, during sleep with the following parameters: ST Menshikov DD. ROHHAD syndrome (review). mode (Spontaneous-Timed, spontaneous- Saratov Journal of Medical Scientific Research synchronized), peak inhalation pressure (PIP) 16 cm 2019; 15 (3): 601–606. h. for example, positive end-expiratory pressure 2. Bougnéres P, Pantalone L, Linglart A, (PEEP) +5 cm of water. V., frequency of 20 breaths Rothenbühler A, LeStunff C. Endocrine per minute. In July 2019, the child was discharged manifestations of the rapid-onset obesity with home in a satisfactory condition with hypoventilation, hypothalamic, autonomic recommendations for non-invasive ventilation dysregulation and neural tumor syndrome in

68 Medical Journal of Zambia, Vol. 47 (1): 63 - 69 (2020)

childhood. Journal of Clinical Endocrinology 8. Lama Aljabban, Lina Kassab, Nour Alhuda and Metabolism. 2008; 93: 3971–3980. Bakoura, Mohammad Fayez Alsalka, Ismaeil 3. Erensoy H, Ceylan ME, Evrensel A. Psychiatric Maksoud. Rapid-onset obesity, hypoventilation, symptoms in rapid-onset obesity with hypothalamic dysfunction, autonomic hypothalamic dysfunction, hypoventilation, and dysregulation and neuroendocrine tumor autonomic dysregulation syndrome and its syndrome with a homogenous enlargement of treatment: a case report. Chinese Medical the pituitary gland: a case report. Journal of Journal. 2016; 129 (2): 242–243. Medical Case Reports. 2016; 10 (1): 93–101. 4. Weese-Mayer DE, Rand CM, Ize-Ludlow D. 9. Goykhman A, Fitch J, Tobias JD. Perioperative Commentary: rapid-onset obesity with Care of a Child with ROHHADNET Syndrome. hypothalamic dysfunction, hypoventilation, and Journal of Medical Case Reports. 2013; 4 (11): autonomic dysregulation (ROHHAD): 710-714. remember your ABCs (airway, breathing, 10. Kot K, Moszczynska E, Lecka-Ambroziak A, et circulation). Journal of the Canadian Academy at. ROHHAD in a 9-year-old boy: a climnical of Child and Adolescent Psychiatry. 2013; 22 case. Endokrynological Polska 2016; 67 (2): (3): 238–239. 226-31. 5. Severinghaus J, Mitchell R. Ondine's curse – 11. De Pontual L, Trochet D, Caillat-Zucman S, et failure of respiratory center automaticity while al. Delineation of late-onset hypoventilation awake. Clin. Res. 1962; 10: 122. associated with hypothalamic dysfunction 6. Amiel J, Laudier B, Attie-Bitach T, Trang H, de syndrome. Pediatric Research 2008; 64 (6): Pontual L, Gener B, Trochet D, Etchevers H, 689-94. Ray P, Simonneau M, Vekemans M, Munnich A, 12. Rapid-onset Obesity with Hypothalamic Gaultier C, Lyonnet S. Polyalanine expansion Dysfunction, Hypoventilation, and Autonomic and frameshift mutations of the paired-like Dysregulation. URL: https://rarediseases.org / homeobox gene PHOX2B in congenital central rare-diseases/rapid-onset-obesity-with hypoventilation syndrome. Nature Genetics. hypothalamic-dysfunction-hypoventilation- 2003; 33: 459–461. and-autonomic dysregulation/ (date of request: 7. Gallego J, Dauger S. PHOX2B mutations and 21.06.2019). ventilator control. Respir. Physiol. Neurobiol. 13. Palchik AB, Kalashnikova TP, Ponyatishin AE, 2008; 164: 49–54. et al. Sleep and its disorders in children. Moscow: Medpress-inform, 2018; p256.

69